Fracture targeted bone regeneration through parathyroid hormone receptor stimulation

Abstract

Disclosed herein includes a drug delivery system comprising at least one peptide and a targeting ligand for bone fracture and/or for bone healing. Some embodiments include a peptide delivery system comprising at least an acidic, basic, hydrophilic, hydrophobic or neutral peptide linked to an acidic peptide or nonpeptidic polyanion for use in targeting the aforementioned attached peptide to a bone fracture surface. In some embodiments, a conjugated peptide expresses an anabolic function that acts through PTH receptor 1, and various formats of targeting ligands guide the drug to raw hydroxyapatite. This system offsets some side effects caused by free anabolic drug, such as high blood calcium concentration

The invention claimed is: 
     
       1. A compound having a structure of:
   X-Y-Z 
 wherein:
 X is a polypeptide having an amino acid sequence of SEQ ID NO: 3; 
 Y is a linker; and 
 Z is a bone-targeting molecule; 
 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. The compound of  claim 1 , wherein Y is a non-releasable linker. 
     
     
       3. The compound of  claim 1 , wherein Y comprises a polypeptide. 
     
     
       4. The compound of  claim 3 , wherein Y is a polypeptide comprising at least 80% sequence identity to amino acid residues 35-84 of a full-length parathyroid hormone related peptide or parathyroid hormone. 
     
     
       5. The compound of  claim 4 , wherein Y is a polypeptide comprising at least 80% sequence identity to amino acid residues 35-46 of a full-length parathyroid hormone related peptide. 
     
     
       6. The compound of  claim 1 , wherein Z comprises not less than 4 and not more than 70 amino acids. 
     
     
       7. The compound of  claim 6 , wherein Z comprises not less than 4 and not more than 40 amino acids. 
     
     
       8. The compound of  claim 1 , wherein Z comprises not less than 6 and not more than 35 amino acids. 
     
     
       9. The compound of  claim 1 , wherein Z is charged. 
     
     
       10. The compound of  claim 6 , wherein at least one amino acid is aspartic acid or glutamic acid. 
     
     
       11. The compound of  claim 1 , wherein Z comprises not less than 6 and not more than 35 glutamic acid residues. 
     
     
       12. The compound of  claim 1 , wherein Z comprises not less than 6 and not more than 35 aspartic acid residues. 
     
     
       13. A compound having a structure of:
   X-Y-Z 
 wherein:
 X is a polypeptide having an amino acid sequence of SEQ ID NO: 3; 
 Y is a non-releasable polypeptide linker; and 
 Z comprises not less than 6 and not more than 40 glutamic acid residues or not less than 6 and not more than 40 aspartic acid residues; 
 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       14. The compound of  claim 13 , wherein Z comprises not less than 6 and not more than 35 glutamic acid residues. 
     
     
       15. The compound of  claim 13 , wherein Y is a polypeptide comprising at least 80% sequence identity to amino acid residues 35-46 of a full-length parathyroid hormone related peptide. 
     
     
       16. A method of treating a bone fracture, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having a structure of:
   X-Y-Z 
 wherein:
 X is a polypeptide having an amino acid sequence of SEQ ID NO: 3; 
 Y is a linker; and 
 Z is a bone-targeting molecule; 
 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       17. The method of  claim 16 , wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to the patient in need thereof orally, parenterally, rectally, or transdermally. 
     
     
       18. The method of  claim 17 , wherein the compound, or a pharmaceutically acceptable salt thereof, is subcutaneously administered to the patient in need thereof. 
     
     
       19. The method of  claim 16 , wherein the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, provides a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, to the bone fracture of the patient in need thereof. 
     
     
       20. The method of  claim 19 , wherein the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, is from about 0.01 nmol/kg/day to about 100 nmol/kg/day.